CZ99599A3 - Peroral preparation with delayed pulsating release and process for preparing thereof - Google Patents

Abstract

The invention relates to an Oral Delayed Immediate Release formulation comprising a compressed core containing one or more active substances surrounded with a coating, wherein release of active substance from the core is caused by rupture of the coating after a definite lag-time, said core comprising one or more immediate release carriers and having no substantial swelling properties upon exposure to gastrointestinal fluids. The invention further relates to formulations containing an Immediate Release formulation combined with one or more Oral Delayed Immediate Release formulations with different lag-times and to a method of preparing an Oral Delayed Immediate Release formulation. The Oral Delayed Immediate Release formulation may be used for the application of active substances whenever a certain lag-time before release is advantageous, such as in the case of anti-asthmatics, anti-emetics, cardiotonics, vasodilators, anti-vertigo and anti-ménière compounds, anti-hypertensives, sedatives, anti-depressants, anti-anxiety compounds, cortico-steroids, general anti-inflammatory compounds, anti-inflammatory compounds for gastrointestinal use, anti-ulceratives, analgetics, anti-aritmics, anti-rheumatics, anti-arthritic compounds and anti-angina compounds. The Oral Delayed Immediate Release formulation may also be used for the application of biological active compounds such as proteins, peptides, enzymes, vaccines and oligonucleotides.

Description

Field of technology. _with

The invention relates to an oral preparation with a delayed pulse release, a method of preparing such a preparation and a combination of a preparation with a delayed pulse release and a preparation with an immediate pulse release. '

Current state of the art.

In general, the goal of any medical treatment is to deliver a certain amount of active substance to the target site in the body, while maintaining the necessary therapeutic concentrations of the active substance at the target site for a certain period of time, and at the same time preventing the occurrence or accumulation of the active substance at a site other than the target. The concentration of the active substance at the target site as a function of time may be of less importance if a therapeutic concentration is reached and not a toxic level. In this case, one preparation can be used to administer the active substance. Sometimes a relatively constant concentration of the active substance may be required, in which case the active substance may be administered in the form of an appropriate sustained-release preparation. However, it is believed that in a large number of situations, a beneficial therapeutic effect can be achieved when the active ingredient is administered in such a way that the administration of the drug is consistent with the variations in the body over the course of 24 hours a day. This goal can be easily achieved by administering a normal immediate-release preparation just before the moment when a high concentration of the active substance is required, leading to a so-called pulsed release of the active substance. However «I »·«· •« · * • « 0 «00 0 • · «0 0 0 » 0 0 ► . · ' « k 0 · « «0 00 · 0 » 0 · .0

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-2-in some cases,-.eg when the specified moment is. during the night or early in the morning, the administration can be carried out during the pilgrimage with an unpleasant burden for the patient. In this case/ but also in all other cases where . the desired improvement in patient compliance (willingness and willingness to take the drug according to the prescription) can be active, the substance is administered through a preparation that releases the active substance after a predetermined delay, i.e.

Tardac;

combination with a pulse-release preparation, . if desired.

There are several methods of formulation of the preparation known, which release the active substance after a predetermined delay time, i.e. -retardation. ' EP 0210540 describes, so-called: . Time-Controlled | AND

Explosion system, i.e. application system, the basis of which is a swelling core and an outer membrane - made of material insoluble in water. - In this system. is a release-mechanism based on the fact that digestive juices 'penetrate' through the cover and allow the 'swelling' substance to swell. This swelling results in the rupture ('explosion') of the package, which is followed by the release of the drug. In the description and claims of the application _; it is -claimed that the retardation of the system can be controlled by the thickness of the envelope. The main disadvantage of this system, however, is that it is not suitable for achieving pulse-release, in combination, with longer (6 to 14 hours) < . those big girls are tall. r. retardation. - Fluctuations in the elasticity of the packaging and non-reproducible swelling of the used .-bob.tne substances. Furthermore, it was observed that the release is not really rapid, but requires several hours (i- to 3). True puisin ..release occurs only, . .when a short' retardation is used. . .

Patent application WO 93/19741 also describes a formulation and dosage form for the time-controlled release of an active substance. In this preparation, the release '-mechanism- is based on the fact., • ·· .·· ···» ·· · »· ··· ····♦ • Λ · ♦· · · · · φ Μ« · · · · · ·♦· ······· ·«··· 4· ·· · *

- 3 that the core containing the active substance is covered with a degradable (degradable) layer or a combination of such degradable layers, while at least one of the degradable layers contains, as the main component, a water-soluble cellulose derivative or a derivative mixture water-soluble cellulose. The disadvantage of this preparation is that it is not easy to prevent seepage during retardation, especially if a longer delay is required. Furthermore, it is difficult to achieve a predetermined retardation, especially longer than. 7 hours,, . which would be reliable and reproducible.'

The essence of the invention

The purpose of the present invention is to provide a dosage form which, releasing the active substance immediately, i.e. pulse in the same way, but after a certain "predetermined" delay time (retardation), without the essential being controlled during the retardation. multiple active substances surrounded by a shell, where the release of the active substance from the core is caused by the bursting (rupture) of the shell after a certain precise retardation time, said core contains one or more carriers for pulse release and has no significant swelling properties at exposure to digestive juices... . .

In an oral preparation with delayed pulse. release, according to the present invention, the release mechanism is based on the fact that. the thickness of the package gradually decreases as a result of seepage. In addition, the retardation should be reproducible, and should be in a 'relatively' simple and cheap way.

This goal can be achieved according to the formulations of the oral preparation

I··» ► * ·

Μ·» · ««

I · · · » »4 · »0949 · · · 449 9*4 · * 4 4 · · »9 49 44 4· · · action of aqueous fluids on the casing material, which ultimately leads to casing rupture as a result of residual pressure in the core tablets. Residual pressure is always present in the compressed core of the tablet and is caused by the pressure used to prepare the core. The difference from EP 0210540 is that the core . of the present invention does not have swelling properties. The retardation before the release of the active substance in the present invention is caused by the essential properties of the shell ans the essential properties of the core, as in EP 0210540. Furthermore, the release of the active substance is caused by the rupture of the shell and not by the gradual dissolution or disruption of one of the main components of the shell, as in - vé .WO·93/19741. . The time of release of the active substance after the rupture of the package depends on ^the composition of the core. The carrier is selected from the group of general fillers and binders, e.g. cellulose. lactose,. mannitol, starch and calcium phosphate .·?Joy improved the disintegration of the core, after opening the package, preferably a small amount of a compound having swelling properties, such as reinforced carboxymethyl cellulose, is added. The overall composition is, chosen so, . that an immediate release carrier is obtained which does not have substantial swelling properties, meaning that the 'carrier composition' has no effect; on system retardation. An immediate release carrier is defined as a carrier causing pulsed release.

The delayed pulse 'release' oral preparation according to the present invention preferably comprises a compressed core f' comprising one or more polymeric materials; -wherein the release of the active agent!substance) from the core is due to rupture of the envelopes· after,· a well-defined retardation, said core'comprising one or more immediate' release carriers and having no substantial swelling properties upon exposure to digestive juices, and . stated'

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999,999 polymeric packaging materials are essentially insoluble and/or insoluble in digestive juices.

Most preferably, it has oral. the delayed pulse release preparation of the present invention is a package that also contains 2-20% of a water-soluble softening agent (plasticizer, plasticizer) and an effective amount of an embrittlement agent. . ...

In this embodiment of the present invention, the release mechanism is based on the fact that the water-soluble plasticizer seeps out of the package. after the tablet is placed in an aqueous fluid (such as digestive juices). As a result of this process, the fragility of the coating layer increases and after a certain time the coating cracks as a result of the residual pressure in the core of the tablet. The retardation of this system can be affected in several ways, namely

when used, stronger si packaging, the dissolution time increases and soaking in water soluble ho 'plasticizers, and -thereby time, when the package bursts when .more is used reagents increasing fragility, packaging will burst sooner or when a larger one is used amount .plasticizers,· will increase time retardation. If on a tablet occur i sharp, edges,, cracking will start

on the edge, which. results in a situation reminiscent of opening the lid of a box (see Fig. 19). When; is·· -"the lid of the box is opened, the active substance is immediately released.'. ...

In order to obtain a preparation in the form of se. reliable retardation and true pulse release, the average is preferably more than 2 . mm and most preferably more than 5 mm.

The packaging material can be selected from commercially available water-insoluble packaging materials, such as ethyl cellulose,

♦ * » ·*·*·« ·* *» other water-insoluble derivatives, celluloses and polymethacrylates. A preferred water-insoluble packaging material is ethyl cellulose (e.g. Aquacoat®). ¹

As already .described -above, . the retardation before the release of the active substance is defined by elasticity. package as a function of time, which is determined by the balance between the type and amount of _{embrittlement} agent and the type and amount of plasticizer for a particular polymer.

Water soluble soften! the agent may be selected from commercially available plasticizers such as triethyl citrate, tributyl citrate and lauryl sulfate, propylene glycol, polyethylene glycol, triaoethine. sodnv. Amount of water soluble

Amount

Even the plasticizers needed depend on the type of compound used. For currently commercially available pharmaceutical plasticizers, the effective amount varies between 2 and 20% of the total solids of the packaging material. Favorable in water. soluble, the plasticizer is triethyl citrate (e.g. Citroflex®} in a concentration between 10% 20% of the total dry weight of the packaging material..

An embrittlement agent is defined as a batch agent that reduces the elasticity of the film that forms the package. The effective amount of embrittlement agent is dependent on the type of agent being used. The effective amount is 20-40%, if talc is used. 3-25% in the case of Aerosil' and. 5-60% .1 in the case of magnesium stearate, whereby - all amounts are to the total dry weight of the packaging material.. -The packaging is prepared in such a way that the thickness of the packaging. remains essentially constant when the product is exposed to digestive juices. Only the softener leaks from the package.

When a package containing a very small amount of embrittlement agent, such as that described in US Patent No. 5,158,177, is used, no rupture of the package occurs.

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and the active substance will be released slowly as a result of the permeability of the packaging. once a sufficient amount of water-soluble plasticizer has been leached. '

To prevent the release of active substances. from the preparation by penetration through the packaging and by diffusion, the packaging should not contain a substantial amount of polymer materials that are soluble and/or disintegrated by the action of digestive juices. Such forms of preparations are described in US Patent No. 4,798,724 and contain a water-soluble packaging material - Klucel®. The disintegration of the packaging in these preparations occurs after they begin to have a digestive effect 'juices. Application EP-. 04-3Γ877 describes a package that is soluble in intestinal juice at a pH value above 5.5, which allows the release of the active substance dependent on the pH value instead of a time-dependent release. Patent application EP 0655240 describes a preparation where the package Yippee. gradually disturbed, - which leads to an increase in its permeability and, as a result, an increase in the diffusion of the active substance through the cover. . .. .

Permeable shells can be obtained when quaternary ammonium groups are present. in polymeric . ' materials of a specific composition, which leads to a prolonged release of the active substance - instead of a pulsed release after a certain period of retardation. Such extended-release preparations are. described, in .patent; application»-EP ..0502-642 . .....

The formulation according to the present invention can be used both for human and veterinary preparations. .

A typical indication, where it will be advantageous to use the preparation in the form according to the present invention, is such an indication when the maximum level of the active substance in the early morning hours is desired. in the case of 'anti-asthmatics' (e.g.

hours,· as bronchodilators), preparations against antiemetics, dizziness and

-cardiotonic, vasodilator, Ménière's syndrome (e.g.

«· ···* • * ♦ ·« *·· • ·' » » ·· ·· betahistine)' and 'preparations' against hypertension. But also for other indications, the use of the forms of the preparation according to the present invention can improve the patient's compliance, e.g. in the case of sedatives such as diazepam, antidepressants such as i.e., fluvoxamine or flesinoxan, 'anxiolytics' such as alprazolam and flesinoxan, or other substances affecting CNS. To other medicines, . which may advantageously be in the form of the present invention, include anti-inflammatory drugs for. gastrointestinal use for the treatment of disorders such as Crohn's disease, ulcerative colitis. colon irritant (such as, for example, mebeverm), '.anti-ulcer and anti-asthmatic drugs, corticosteroids'. such as prednisone or other anti-inflammatory drugs, analgesics, antirheumatic drugs, . anti-arthritis and anti-anginal drugs. . . · <

Another class of active substances for which -is. advantageous formulation into the preparation with delayed pulse release according to the present 'invention' are bioactive proteins, peptides, enzymes (e.g. pancretam), vaccines (e.g. anti-influenza vaccine) and oligonucleotides. Very often compounds of this type are not sufficiently resistant to the very acidic environment of the stomach. In addition, it may be desirable to administer an agent of said type in a pulsatile manner as recently described. Cardomone et al. (j. Contr. Rel. 1997, '47, 205-219) for an application system, for' immunization against' t-eLan toxin. ' . ' '

It is possible to further improve the patient's compliance by combining a product with different retardation times in a single dosage form. So the present invention also refers to such a preparation, when the preparation with delayed pulse release, has. certain time of retardation and is combined in one capsule with a preparation with (immediate), pulse, release and/or with a preparation with delayed pulse release, or with several such preparations, with a different retardation time. The capsule can

- 9 • ta ·· ·♦·· ·· ·* • * * · a· * a · · · a « a ·« « «·«« • a a a t * · ·. · · · ♦ · ♦ a a a a a a a a a a a a a a a a· * · · · · be 2 of the usual material such as gelatin or starch derivatives. In an alternative unit dosage form, the preparation according to the present invention is surrounded by the preparation, with pulsed release. -Thus, the present invention 'also relates to a delayed pulse release formulation· where the delayed pulse release formulation is surrounded by an (immediate) pulse release formulation. ' ' .

The present invention further relates to the use of a combination of several active substances, core forming substances. or substances creating . package, for ^: the production of a delayed-'pulse-release preparation, which comprises a compressed core surrounded by a package, wherein the core contains one or more active substances and one or more carriers for (immediate) pulse release, and where the -released active· substances it is caused by the rupture of the outer cover (membrane) after a certain delay time.

The present invention also relates to the method of preparation of the preparation with delayed pulse release described in the preceding text, which method consists in

1) squeezes out the core of active substances by uls release and from a mixture containing one or several and one or several carriers for (immediate)

2) the pressed core is coated with a mixture of packaging materials, while both the core and the packaging have the properties described in the previous text. ·..·

As already mentioned, the preparation ' with delayed pulse releases can be. combined, with preparation with (immediate) pulse release. -or With a delayed pulse release preparation with a different retardation time in one 'embodiment.' Therefore, the present invention also relates to a method of preparing a preparation with delayed pulse release, which consists in the fact that *· ··*·

- 10 * > · * 4 ·· *· • 9 · * » . · · ·

I · · · «90 990 • · • · · ·

1) a core is pressed out of a mixture containing one or more active substances and one or more carriers for '- (immediate·) pulse release,·

2) the pressed core is coated with 'one..' or several packaging materials, . · ' 3) the first preparation with (immediate) pulse release

i) is combined in one capsule with the preparation..

with (immediate) pulse release and/or one or several. preparations, with delayed. by pulsed release with different retardation times, or ý ' ii) is ' surrounded by the preparation. - with pulse release and a mixture of packaging materials, ..

wherein- both the core and the shell have 'the properties and/or composition described in the preceding text.' .

The advantage of the preparation according to the present invention is that it can be formulated using commercially available materials - and in addition, in a relatively simple and inexpensive way.

. . The invention is described in more detail in the following text in the form of examples. ''

Examples of embodiments of the invention'

Example 1.-Several were prepared. coated, tablets with different amounts of carboxymethyl cellulose to determine the effect of cross-linked carboxymethyl cellulose on the tablets. with the core. Tablets 'were. manufactured by the following; in the manner of: .

1) microcrystalline cellulose was "granulated" with the addition of an aqueous solution of betahistine 2HC1 in a high-speed mixer.

2) the yield of step 1 was dried and sieved • 999 ·····♦* ' 9 ' *9 9 9 9 9 ·9 9

999 999 · 9 99* 999 ,«9«β·>90 «II «9 99 99 9* 99

·.'·. - Η 3) the yield of step 2 was 'mixed' with the talc · and optionally; with cross-linked carboxymethyl cellulose

4) the yield of step 3' was pressed into tablets with a diameter of '5 mm and a weight of 100 mg'

Tablets were wrapped in the following way:

.5) The packaging suspension was prepared by mixing ethyl cellulose, . softener and embrittlement agent in the described ratio with water until a suspension with a dry matter content of 20% was obtained. · · ' .

6) In a coating drum or fluid device, the yield of step 4 (tablet cores) was coated with the yield of step 5 until the desired weight was reached.

After coating, tablets were obtained, the composition of which (in mg per tablet) is shown in the following table.

Excipient . Try. with b C d E L Core '. '' . . betahistine; 2KC1 27.8 . 27/.8. 27.8 27,,8 .27.8 27.3 mi crocrystalline cellulose 69.2' 67.2 65, 2 65, 2 64,.2 62.2 tallow 3/0' 3, 0 3, 0 3.0- '. 3-, 0 3, 0 cross-linked. carboxymethylcellulose for . oh oh 2.0 .4.0' 4,-0,. . .5.0 7.0 Cover '. ... .· ethyl cellulose ' . 14.3 '14.1' 14.5- 14.1 . 14.3.' . 14.5 Citrořlex© 2' '3.0 '3.0 '3.1 3.0 ' 3.0 ' 3.1 ' talek' - 8, 6 8.5' ' '8/7 8.5 ' 8, 6 8.7 in total 125', 9,' '125, 6 126, 3 125, 6 125, 9. 126, 3

• BB Β * « ·«' ΒΒ·β Μ • Β ·

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ΒΒ Β Β . The dissolution test was carried out using a USP II device with a half exchange of medium and a stirring speed of 50 rpm. The results are summarized in the following table.

Tablets with -j core packaging(%) average time .. release (n=S) try amount cross-linked carboxymethyl cellulose (%) 1 and ' 0' · / 2Ό, 5' 7.2 hours b- .2 20, 4 6.0 hours C d 20, 8 7; 0' hours - d 4. \ 20.4 7.5 hours O 5 20/5' .· 7.6 hours L '·; ⁷ . . . 20.3 7, '5 hours

From the mentioned experiments, it can be concluded that the addition of a strong developer has no significant effect on the retardation time.

and

Example 2 '

Tablets were prepared in the same way as in example 1 in the experiment and by the procedure described in example 1, but they were covered with a thicker packaging layer. The composition of the tablets (in mg per tablet) is given in the following table:

bxcipient : Example 2 'The core . , betahistine; 2HCl •27.8 ,'microcrystalline cellulose 62.2'' this.k 3.0 cross-linked carboxymethyl cellulose 7.0

• 0 00*0 ·· • · · '1 ·· 00 » 0 0 · » 0 0 · ··* ·· ·

- «

0« 0 0

- 13.-

Packaging ethyl cellulose . 19, 6 .Citroflex© 2 4.1 ... a plate. . 3,.9 'total' ' ' 12 /, 6 , ,j

The in vitro dissolution test with 6 coated tablets was carried out on the ÚSP II device with water as a solvent, and a stirring speed of 50 rpm. The results, also shown in Fig. 1, are tabulated. ,

c. reed- i.u released ( .%) in the outlet in time (v hours) 7 3 G 1.0 11. 12' 13 14 Ϊ 3 1S 1 '' ^: o 0 0 ⁰ .0 '0 10 0'. ' 100 100 2 ⁰ 0 . 0 . 0 0' O 0 5 S 100 3 0 0 '0 0 O 0' 0 0 0 o' 4 0 , 0 0 about . 0 100 100 ,100 ..100 5 0 0 O 0.· 23 100· 100'' 10.0 1-0 0- 5 0 . 0 0 '0 100 . 100 100 100 100

The conclusion from these experiments is that a thicker package combined with a lower amount of ^{embrittlement} agent leads to a longer retardation time.

Example 3 ' ' . ,

Tablets with a core were prepared in the same way as in Example 1 in Experiment 1 by the procedure described in Example 1, but they were coated with a suspension containing a lower amount of talc. The composition of the tablets (in mg per tablet) is given in the following table:

·. ·* «« ···« ·· ·«« « « · · · · · · • « · » · « .· · · . * « ·*« · · · « · *·· ··♦ • · « · · · · * ·«* ·· ««.«* »· «·

- '14- -

Excipient Example 3 core' betanistine,2HC1' 27.8 microcrystalline cellulose /62.2 tallow 3, 0. . . cross-linked k. carboxymethyl celluiose 7.0 Packaging · . ethyl cellulose 17.6 Citroflex © 2 3.7 - ' tallow -v. 5.3 - ^- -!- ¹ -- total .··'·.· 126.6

The in-wind dissolution test of 5 coated tablets was performed on a USP II device with water as the dissolution medium and a stirring speed of 50 rpm. The results,' also shown in Fig. 2,. are listed .in the table.'

C, channel. release (%) in sampling time (ν' hours) 7 8, Q 10 11' 12 13 14 15 16'. and 0 ⁰ 0 ^; 84.. .100' '2 0- . ·. 0 0 ' , 9 100 '3' ' about . 0' 0 .0 '100' 4. 0 0 . 0/ 100- 100. '5 0 , 0 .. '0. 0 100 δ , 0 • I .O 24 10.0 100

The conclusion from these experiments is that a lower amount of embrittlement agent leads to a longer retardation time.

• «ν «a «>· aa aa aa aaaaaaaaaaa « * · 9 aaaa a aaa aa · aa ··· aaa a- aaaaaaaa aaa aa a· «a ·· aa .5 Example 4 ^f , · I ·· They were prepared .tablets with the same core as in example 1 in experiment f by the procedure described in example 1, but they were coated with a suspension containing a larger amount of talc. The composition of the tablets (in mg per tablet) is given in the following table:

excipient- Example 4 J Core. - · ' ' ' betahistine.2HC1 year .27.8 microcrystalline cellulose 62.2 tallow 3.0- cross-linked carboxymethyl cellulose 7.0 Packaging ethyl cellulose 16.2 Citroflex® 2 3.4 talek' 6, 5. in total 126.1.

Dissolving. the in-vitro test with 6 coated tablets was performed on a USP II device with water as the solvent medium and rotational speed. stirrer, 50 rpm. Results·, also '.shown.. 1 in Fig'. 3, are listed in the table.

C. hen- lu release - (%) in sampling time (hours). ; / 8 9 10 11 12 · 13 14 15 16 1 .· 0 .0 '59 100 100 / '2 . ⁰ 0. 0 71 100 3 0 o' ; 12 100 100 . 1. 4 '0 ⁹⁷ 100 ' 100 100 . 5 0' . 0 0 58 100 6 ^{0 78} 100 100 100

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4 4 4 • 44 -444 • 4 «4 4 4

The conclusion from these experiments and the experiments shown in Examples 1 and 3 is that the pre-release retardation time can. be affected by the amount of embrittlement agent.

Example 5 Tablets with a core were prepared in the same way as in Example 1 in the experiment using the procedure described in Example 1, but they were coated with a suspension containing a larger amount of talc. Composition of tablets (v-.mg. per tablet) . the following table shows: . ' .

Excipient Example 5 core betahistine.2HC1, 2Ί-, 3 microcrystalline cellulose ' 62,,2 Lflc.k 3.0. reinforced, carboxymethyl cellulose ?; about . . Packaging , . ethylcel.ulose ' . 15.1' Citroř.lex® . 3/2 quiver 7.6 in total 125.9

In vitro dissolution test with 6.' carried out on USP· equipment. II with water and a rotational speed of the stirrer of 50 rpm, in Fig. 4, <j,are given in the table.'..

coated tablets; was as a dissolution medium Results, also shown

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4 4 4 4 • j 4.1 444 444

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number channel release ( %) in-subscription time (in hours) 7. δ 9 . io '11 12 13 14 15 16 - ’ 1 0 about ; . 100 100 100 2 0'. 0 '87 100 100' • 3 0 40 100 100 100 4 0 . O- 10 100 100 5 0 0 0 100 100 and'- 0 0 0 100 100 100

The conclusion from these experiments and from the experiments described in Examples 1, 3 and 4 is that the retardation time before release can be influenced by the amount of embrittlement agent.

Example 6

Core tablets were prepared, as in Example··!

' * in trial f by the procedure described in example 1, but were coated with a suspension containing a larger amount of talc. The composition of the tablets (in mg per Jean tablet) is given in the following table:

Excipient ¹ Example '6 'Core , , betahistine.2HCl 27.8 microcryst.aiic cellulose '62.2 plate. ' 3, 0 crosslinks carboxymethyldelulose 7.0. Cover... ethyl cellulose "· , 15.1 C-itroflex® '3,'2' , tallow. ' . 7.6 total' .12 5.9

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The in vitro dissociation test with 6 coated tablets was performed on a US? II with a half exchange. media (pH = 1.2 and then . at = . 6. 3) ' and at a rotational speed of the stirrer ·50 rpm. The results, also shown in Fig. 5, are tabulated.

number . channel released ( %) in c sampling time (in hours) 7 8' 9' . ¹⁰ ' 11 . 12 13 14 15 16 1 0 0 92 ¹⁰⁰ 100 2 0 0 8.2 100 . 100 ³ ' 0. - 0' 32 100 100 4' 0 0- '99 100' 100 . . . 5 0 0 100 ,100 10 0' 6. 0 0 . 25 100 100

The conclusion from these experiments and from the experiments described in Example 5 is that the preparation according to the present invention can be prepared in a reproducible manner.

Example -7 .'

Tablets were prepared with a core of the same composition as in Example I in experiment f by the procedure described in Example 1-, but were . coated with a suspension 'containing magnesium stearate' as * . .

embrittlement agent instead of talc. - Ingredients '; tablet (in mg per tablet) is given in the following table:

Excipient Example 7 Core betahistine.2HC1 27.8; microcrystalline cellulose 62.2 tallow. 3.0. .'7 cross-linked carboxymethyl cellulose 7.0.

* ·« ··«. · ·♦ • ·· · · · · ·· ♦ · · · « · a · · · a ««e « a * « a a »«» .»·♦ « ·«··· · · «·« ·· · *' · *l · · a ·

- 1S -

Packaging. ' ' ethyl cellulose 13.1 Citrophy.x© 2 ' '2.8 Mg. stearate 3.9 -ee-l-k-em——— ' , 119.8'

Dissolving. an in 'vitro test with 6 coated tablets was carried out - on the device, US? II with a half change of medium .'(ort = i, 2 .and then pH = 6.8). and the rotation speed of the mixer 50.' 'rpm.

The results ^, also shown in Fig. 6, are tabulated.

number channel . release (' %) in the sampling no ise .(v hours)., 1.0 1.5' '2.0. 2.5 3.0 .2.5 ' 4-.0/ 4.5 ' 5.0 5/5 . .1 0 0 .0 0' 100' 100 . 100 2' 0 0 . 0 0 0 0 . 100 . 3- 0' 0 0 0- .· 99 100 100 ' 'P. d 0 0.' O 0 33 100 100 5. 0 0. 0 ⁰ ' '100 100 1.00 am ,5 . 0 0 16 30' ,94 íob. 1Ό0

The conclusion from these experiments is that the type of agent causing brittleness in the package has; significant effect on the retardation time before drug release. , '

Example 8

Tablets were prepared with a core of the same composition as in example 1 in experiment f. by the procedure described in example 1, but they were · coated with a suspension containing triacetyl.glycerol as • 0

- 20 0 00 00 0000 00 000 0 0 0 0 · 00 0

010 00 0 0000

9 0 9 0 0-0 00 0 0 · 000

0 0 0 0 0 * · 000 0· 00 0« 00 0* emollient instead of C.itrof lexu©.. 'The composition of the tablets (in mg per tablet.) is given in the following table·;

Excipient Example 8 Core. bethehistine.2HC1 27.8. microcrystalline, cellulose 62.2 butt. ' 3.0 reinforced carboxymethyl cellulose 7.0 Packaging ethyiceluiosis 14, 1 triacetylglycerol 3.0' talc' 8.5' in total 125, S

Dissolution test in. vitro 'with 6 coated tablets was carried out on the device US? -ΊΙ. with a half exchange. media (p.H = 1.2 and then pH = 6.8) and a stirrer rotation speed of 50 rpm. The results, also shown in Fig. 7, are tabulated.

number channel release ( %) in the Withdrawal time (in hours) 1.0 1.5' O. 2.5 3.0 3, 5 4.0 4.5. 5, 0 5.5 * ' i·' 0, 0 100' 10-0 .2 0 0 100 100 O- 0' 100 100 4 0 Ό' 100' 100 "5"; ' 0 , 0 100 100· 6 0 '0 98 100

The conclusion from these experiments and the experiments in example 1 is that the type of plasticizer in the packaging has a significant effect on the retardation time before the release of the drug.

- 21 • ·· »» ··♦· ·· · ♦ » » » · * « » * » * « · · ♦ ···· • ··· · ·; · · · ',··* *·· • ·· ·*· « « >»«·· · · ·· · « * »

Example 9

Pollen prepared tablets with a core of the same composition as in example 1 in the experiment and by the procedure described in example 1, including the coating. Ingredients . tablet (ν' mg per tablet) stated in the following table: '· '

Excipient '.Example 9· . Core! betahistine ,'2HCl 28.8 microcrystalline cellulose 68.3 tallow ' 2.9 cross-linked carboxymethylcellulose. . 0 Packaging. ethyl cellulose. · 1-4,1 ... triacetylglycerol 3.0 L 3 Σ Θ 8.5. ' in total 125.6 I

. In vitro dissolution test se. 6 coated tablets, was performed on a .USP-.II apparatus with a half-exchange of media (pH = 1.2 and then pK = 6.S) and a stirrer rotation speed of 50 rpm. The results, also shown in Fig. 8, are tabulated.

channel no release ( %) in withdrawal time (in hours) 7.0' 7.5 8.0 8.5 5.0 9.5 10,.0 10.5 11, 0 11, 5 12.0 12.5 13, 0 1 0 0 . 0 O; 1.6 57. 80 9.2. . 99 100 .2 .0 'Ό. '0 0 . ¹⁹ 57 . ,79 .90 97 100 3 0' 64 . 91 100 100 100 100 100' 100 100 , ⁴ about ·' '0 0. 35 35' 83 93 98 100 100 .5 O '0 ' 0 . 0 0 70 87 94 '1 a.m 100 6 0 0 0' . 30 '30' 84 94 '99 100 and 0.0

• *9 9« «999 9* «9

9 9 · ¹ * 9- 9 99 9 '9 99 99 9 9999 «94 999 99 *99 99*

99999 9 9

99**99 99 99 99 9«

- 22 The conclusion from these experiments is that the absence of even a small amount of swelling agent leads to a slower gradual release of the drug after retardation.

'Přrktad ^- íů

Tablets with the same composition as in Example 1 were prepared in experiment d by the procedure described in Example I, including the packaging according to Example 1. The composition of the tablets (in mg per tablet) is given in the following table:

Excipient Example 10 Core '. ¹ .·. betahistine.2HC1 . . 27.3 microcrystalline cellulose '65, 7 tallow. ' 2.8, cross-linked carboxymethyl cellulose 3.7 Packaging. ' ' etvlcellulose 14.2 Citroflex © 2 .-3.0 talc'· 8.6 total·' 12 5.9

Dissolution test ·. in -vitro with 6 coated tablets was performed on . device USP .II 5'half' exchange of medium (pH = 1.2' and. lever pH. = 6.8) and a rotational speed of the stirrer 50 rpm: Results, also shown in ob.r. 9, are listed in the table.

- 23 • « • 9

999 · 9 .

. ·» ··«· · 9

9 9

9 9

9 9 9

99 ·· * · · >

• · · · • 9

99

No. downpour release ( %) in sampling time (in hours) 7.0 7^5 3.0, 8.5 9.0 9.5 10·, 0 10.5 11.0 11.5 12, 0 12.5 13.0 1 '0 0 '0 0 69 100 100 100 2 0 0 0 sd ICO 110 10 Γ0Ό O '0 0 O, C 32 100 100 . 4 0 0 0 0 0 '0 72 100 • 5 0 27 100' 100' 100 ' 100 100'. 100' 6 0 '' 0 '' '0 0 33 93 100. 100-

Example 11 Tablets of approximately the same composition as in Example 1 in experiment f were prepared by the procedure described in the example. 1, including the packaging according to example 1. The composition of the tablets (in mg ría one tablet) is given in the following table: ' ’ ’

Excipient Example 11 Core · betahistine.2HC1 27.8 microcrystalline cellulose 62.2 tallow ..·.. 3.0 cross-linked carboxymethyl cellulose . cover' ethyl cellulose _; 14.5 Citroflex® 2. ' 3, 0 tallow - ⁸ ' ^{7 :} ·. in total ,126.2

The in vitro disintegration test with ·6 coated tablets was performed on a USP ,.ΊΪ apparatus with a half exchange of media

AA

II A A·A

- 24 AAA AAA A A A A A A *

A AAA·

AAA AA A A «Α

AAA ···

And «

AA AA (pH = 1.2 and then pH = 6.8) and at a rotational speed of the stirrer of 50'rpm. The results, also shown in Fig. 10, are tabulated.

channel no release ( %) V wait over time (v him into .purple) -1, -0 8.,.CL 8.-,5 9.0 9.5 10.0' 10.5 11.0 11.5 12.0 12.5 13, 0 1 0 29 93 100 .1-00 2 0 •0 95 100 100 3 0 0 83 100 100 1 4 .0 0 0 80' 100 5 0 0 0 100 100 6 0 70 100' 100 100 ·

Example 12. ' . ' '

Tablets of the same composition as in Example 1 in Experiment f were prepared by the procedure described in Example 1, but with a larger amount of packaging material of the same composition as in Experiment f of Example 1. The composition of the tablets (in mg per tablet) is given in the following table:

.Exciting Example 12 Core bet5.histin.2HCl _: 27.8 microcrystalline cellulose 62.2 - .. tallow 3.0 cross-linked carboxymethylcellulose O. Packaging. ' ' ethyl cellulose. '21.2. Cítroflex® 2 4.5 talc- 12.7 in total 138.4.

- 25 • ·« · • »· • · · 9 · * · 9 9 9 · • · · 9 9 . · 9 · 9 9 • ·9 · 9 · * · · · · · · 9 · • 999·· · · ··· «· «· «· · · ·9

... The in vitro dissociation test with 6 coated tablets was performed on a USP II device with a half exchange, media (pH = 1.2 and then pH = 6.8) and a stirrer rotation speed of -50 rpm; Vý-sTe/ďkyj ^- tffktÉ-ž-rrkérsrr^-rta—obrn—Rrjsou—uv-ede-nv—v— babu-tee-i-

No. downpour. release (% in 'subscription time' (in hours) .9.0 3.5 .10, 0 .10.5 1.1, Fr. 11.5 12,.0 12,.5. 1.3.0. 13, 5 '14.0 .14.5 1 O 0 0 9 7 3. 100 2 0 14 100' '100. 100 100 .3 - 0 5 6' 100 100 100 100' 4' . about . 0 0 J 7 4 100. 100 5 0' 0 29 100' 100 100. d 0 0 ,1 0 Ί U '82 . 100 100

The conclusion from these experiments is that the stronger the cover. of the same relative composition as in example - 1 leads to a longer time. retardation.

Example 13 ' , 'Tablet cores with the composition as in example 1' were prepared in ρ-piece c . by procedure. ..described. in_.example , 1, with.'smaller amount-· packaging material, as it is. . described in experiment c of example 1, namely in the amount of 100,000 (10 kg) coated tablets. Composition of tablets (in mg per tablet) ί

the following table states:

• φ» 4 · 4 444 44 44

4' 44 44 4 4 4 4 4

4 4 44 4 4·44 *44 44 4- 44 444 4*4

4*444 4 4

44444 4·44 44 44

Excipient 'Example 13 Core betahistine .'2HCl 27, 8 t microcrystalline cellulose 6572 tallow 3.0 cross-linked carboxymethyl cellulose 4.0 - Cover ethyl cellulose - 9.0. Citroflex© 2' .1,-9 tallow 6.8. in total 117.7

The in vitro dissolution test with 6 coated tablets was carried out on a USP II device with a half change of medium (pH = 1.2 and lever pH = 6.8), and a stirrer rotation speed of 50 rpm. the results, also shown in Fig. 12, are tabulated.

hmm- downpour release (%) in the sampling time (in _t hours). 7.0 7.5 3.0 9.5 9.0 3.5 10.0 10.'5 11.0 11.5 12.0 12.5 1 0 0 83 100 100 100' 100 100 100 ' 2 0 .0 0 0 91 ok 100 100 100 3 O 0 0 '79 100 10 100' _t 100 100 . 4' 90 100 100 100 100 100 100 '100 100 5 0 0 0 0 40 . 70 ³⁷ 94 100 6 About ⁰ '0 51 100 100 100 100 100. 100

The conclusion from these experiments is that the preparation according to the present invention can be prepared in an amount of 100 00Ό (10 kg) coated tablets.

Β ΒΒ

ΒΒΒ Β Β

ΒΒΒ Β

Β Β ΒΒ Β Β

Β Β Β β Β Β * · • Β BBBB

ΒΒ ΒΒ Β Β Β · « Β

Β Β . Β Β Β Β Β Β ΒΒΒ ΒΒΒ

ΒΒΒ Β Β

Β Β Β * Β Β *

- 27 Example 14

Tablet cores were prepared with the composition as in Example 1 in the experiment, with the procedure described - in Example, 1, with a smaller amount of the product described in Example 1, namely ¹ in the amount of 500,000 (50 kg) coated tablets. The composition of the tablets (in mg per tablet) is given in the following table: ·' . ^j ,

Excipient Example 14 core' betahistine. 2HC.1 '27.8 microcrystalline cellulose 65.2 plate .3.0 carboxymethyl cellulose cross-links 4.0 ' ' Cover . ethyl cellulose 10.3,. Citroflex® 2 2.2 o a 1 e k · , , ^Ί,Ί ' in total 120.2.

An in-heat dissolution test with 6 coated tablets was carried out on a USP II device with a half media exchange (pH = 1.2 and then pH = 6.8) and a stirring speed of 50 rpm. Results, also shown in Fig. 13, are listed in the table.

No. ka-. downpour release (%) in sampling time (in hours) 7.0' 7.5 8" 0 8.5 9.0 9.5 10.0 10.5 11, 0 11.5 '12 _r.O 1 0 77 100 100 100 100 2 .0- 0 0 61 100 100. 3 0 , 0 39 J00 100 100 4 0 0 0 81 100' 100 5 - 0 0 0 - 0 0 100 ⁶ 0 21 100 100 1Ό0 100

«4 *·*4

The conclusion from these experiments is that - the preparation. according to the present invention, it is possible to prepare 500,000 (50 kg) coated tablets. ,

Example 15

Was;

oroveaena research three-way cross. bioavailability study, the objective of which was to investigate the rate and extent of absorption of betahistdn after oral administration in a conventional formulation or in an oral formulation with a delayed pulse release.(TS.R) . In addition, the safety and 'tolerance' of preparations with betahistine were also evaluated.. TSR . were in the form of a gelatin capsule containing

Preparations of immediate-pulse-release preparations and delayed-pulse-release preparations according to Example 11 (TSR(0/8)) or Example 12 (TSR,(0/12)).

·. The group of subjects consisted of 8' healthy men aged' between

- »· i'r years with a weight from 60 to 95 k-g. Subjects' suitability was assessed based on clinical laboratory examination, medical history, vital signs, ECG and drug addiction test.

Four types of treatments were performed: ' ^{: 1}

I. conventional 24 mg preparation at time t = 0.h' and -ť ~ 8h

- — --II, conventional 24 mg-preparation ť'='0'h ' and t12 h ' '' '

III. preparation TSR (0/8) C '48 mg at time t =' 0 h

IV. preparationTSR(0/12)D 48 mg at time l = '0 h.

Treatments were performed in such a way that 4 subjects were subjected to treatments I and III and 4 subjects to treatments II and IV. '

The washout period between treatments (morning dosing) was 48 hours. The total duration of the study was 8 days. Samples, urine were collected 'before each 'dose and then 'fractions were collected after 2 hours - up to 18 hours, and' 18-24/ 24-36

4 4444

4

4·4 4

4 4 4 4 4 • 444*4 * 4.4 · 4 4 4 «

444 44 44 44

- 29 and 36-43 hours after each dose. Safety evaluation was performed once during the study and once after its completion.

Urine samples were analyzed for the concentration of 2-PAA, the main metabolite of betahistine, Pro. for each type of '· treatment', cumulative 2-PAA excretion values were calculated. The results showed that preparation C (treatment III) led to the release of one dose just after administration and to the release of the second dose 12 hours after the first dose.

"Fig.'14 shows that the urinary excretion profile after treatment of type ¹ ' _r . , > III is comparable to the post-treatment profile of type II in which conventional 2x daily tablets were administered. Data- on safety and tolerability .showed that 'all types of treatment were. well tolerated.· All ' subjects completed the study. . From a 'safety' point of view, no clinically relevant features emerged.

Example 16.

To verify the possibility of administering prednisone in the form according to the present invention, the cores of tablets containing prednisone were prepared according to the procedure described in example 1, and they were coated as described in example 1. Composition, tablets (in mg per tablet ) the following table shows:'

Excipient Example.16 .; Core. prednisone 4.2 microcrystalline cellulose 132.'4 talc' 4.1 cross-linked carboxymethyl cellulose 5.4

i»,

·> «» ·· ·

Packaging ethyl cellulose 23.4' Citroflex © 2 4.9 talc' 14.1' total ' ' . 188.5

. The -in vitro dissolution test with 6 was carried out on a USP ..II device with water and a stirrer rotation speed of 50 rpm. on. Fig. 15, are listed in the table.

coated tablets'., was as a dissolution medium Results, also . shown

minor a dream release-'. ( %) in collection time (in hours) 5 5.5 6 c, 5 7 7.5 3 '3.5 9 9.5 10 10.5. 11 1 . '0 0 0 0 0 .' 0. 0 0 0 • 0· 0 0 0 2' 0 0 0 0 87 98 100 100 100 100 100 100 100 3 0 0 '0 0 0 99 -100. 100 100 100 100 100 100 . Δ 0' 0 0 0 0 100 100 100 100 100 ' 100 100 100 5 0 0 0 . 0 ' 4 9 100 100 100' 100 100 1-00 100 100 6 '0 0 0' 50 97 100 100 100 100 100 100' . .100 100'

The conclusion from these experiments is that it is possible to prepare a prednisone oral preparation with delayed pulse release according to the present invention.

Example 17, '

To verify the possibility of administering flesinoxan in the form according to the present invention, tablet cores containing fexinoxan were prepared according to the procedure described in example 1, and they were wrapped

and - Ch • 44 4 4 4 4 • · fl 4. β β Β· • 4 • · 4 4 4 4 » 4*4» »4 44 • * · · 4 4 4 4 4 · · · · · »4 4 44 4 4 4 4 and 4 4 « * 4 4 « 44 44 44 44 is described in Example 1 Ingredients tablets (v mg to one F tablet)' states the following .table:

Exciplent Example 17 Core flesinoxane 19.9 microcrystalline cellulose 70.4 this.k .4,5 . ' cross-linked'carboxymethyl cellulose 3', 5 . Packaging- cellulose. '' 20.2 Citroflex © 2 4.2· tallow 12.1 total . 134.8

Dissociation test in vitro. with 6 coated tablets was carried out on a USP II apparatus with water as the dissolution medium and a stirrer rotation speed of 50 rpm. The results, also shown in Fig; .16, are listed in the table.

e forests noxan release {%) in sampling time (in hours'} and 2 3 4 5' 6 7 WITH 9 10 11 12 13 1 0 0 Q O; 0 0 56 89 . 94 96 97 99 100 2 0 0' 0 0 0 0 0 75 93 95 93 97 97 3 . 0 0 0 0' 0 0 0 94 99 97 97 93 93 4' 0 . 0 - 0 0 0 0 0 82 105 107 107 108 108 5 0 0 0 0 0 0 0 90 96 95 97 93 93 6 0 0' 0 0' 0' 0 0 ; 92 23 ⁹⁸ 100 . 102 102'

• 0 0 • * · · • Mt

0 • 00 · · .

··· ·

0«

0· 0· «» 0

0 0

00« »00 • 0

0 0 0

- '32 The conclusion 'from these experiments .is that' it is possible. ' to prepare a lesinoxane oral preparation with delayed pulse release according to the present invention.

Example 1'8

To verify the possibility of administering diazepam in the form according to the present invention was. prepared tablet cores containing diazepam by the procedure described in example 1, and were coated as described in example 1. The composition of the tablets (in mg per tablet) is given in the following table:

Excipient .Example 18 - Core' diazepam. 3 „ 6 . microcrystalline cellulose 10 3.0 tallow 3, 5 cross-linked carboxymethyl cellulose 4.7 .Cover ' , ' ' ethyl cellulose ' ' ' ' 1.4, 8 Citroflex® 2 '3.1'·' ' talek ’ . ' 8,9 total . 141.6.

An in vitro dissolution test with 6 coated 'tablets' was performed on the device. USP II with a half medium exchange (pH = 1.2 and then pH = 6.8) and a stirrer rotation speed of 50'rpm. The results, also shown in Fig. 17, are tabulated.

. 99 • 9,9999

99

9 9 · 9

9 9 9 9 '9 99 9 9 9

9 · 9 9

999 99 99

9

9 · 9 9

9 9 9

9* «99,999

9#

99

Diaz release.( %) .v - take off at the same time (v hours) remember 5. 5 and 5 with 6, 5 7 7.5 0 at 8.5 C 9.5 10 10.5 11 1 0 0' 0 . 0 . 61' '85 39 90 90 - 90 90 90' 9.0 2 ,0 0 .. 0 0 53' 73 83 '84 8 4 34 34' . 84 84 . ·3- - about - 0 JJ 0 0 0 . 81 99 100 100 ioo 100 100 4 0 . .' 0- . 0 O 0 0 64 73 33 90 91 91 91 5'. O 0 O 0 '0 0 0 0 42 86 87 87 . 37 6 0 0- 0 - 0 . 0' 0- 0 73 91 97 37 97 97'

The conclusion from these experiments is that it is possible to prepare an oral diazepam preparation with a delayed pulse release ¹ . Even according to the present invention.· .

Example 19. ..

To verify the possibility of administering "mebeverin" in the form according to the present invention, tablet cores containing mebeveriri were prepared by the procedure described in example 1. and were coated as described in Example 1.' The composition of the tablets (in mg' per tablet) is given in the following table;.

excipient - Example 19 Core ^- ' mebeverine 38.6 • mi-kr© crystalline cellulose - 3 6.0 - talc' 4 / 7'' cross-linked carboxymethyl cellulose what -r Packaging ethyl cell. losis 12/b' Cit-roflex© 2 2,6- tallow . 9-, 4. - total / 128.7

• ·* ·Φ • · · 0 . · » * · 0 · · 0

900 «· 9

0-000 0000·00

0000 00 00 0 0 0 0 0

0 0 0 0

0,000,990

0·00 00 00

- 34 The in vitro dissolution test with 6 coated tablets was carried out on a USP II device with a half change of medium (pH = 1.2 and then pH = 6.8) and a stirrer rotation speed of 50 rpm. The results, also shown in Fig. 18, are tabulated.

It doesn't work. ΓΪ.Γ1 release (¾ in sampling time (in hours) 7.0 S, 0 9, 0 10.0 11.0 12.0 13.0 14.0 15, 0 16.0 1 0 0 0 , 0 0 33 63 69 . 74 '7 3 2' 0 '0 0 0 0 0 6 70 78 .82 3 . .0 0 0' 0. O 0 '40 69 77 81 d' 0· 0' '0 0 0 0 0 '59 91 98 5 0 0 0' 0 0 0 . 57 63 63, 73 6. 0 0 ^; 0 '0 0' 0 7 59 70 74 73

.in.

The conclusion from these experiments is that it is possible to prepare a mebeverine delayed pulse release oral preparation according to the present invention.

Example.20

To verify the possibility of administering the vaccine in the form of the present invention, tablet cores containing the influenza vaccine were prepared by the procedure described in Example 1 and were coated as is. described in 'example' 1'. - The composition of the tablets (in mg per tablet) is given in the following table:

Excipient '' Example 20 core' flu vaccine (bioactive protein) 0.325 microcrystalline cellulose 105.1 tallow 0.6.' cross-linked carboxymethyl cellulose .6,7 .

«9

9 9 «

9* ' « 99

9

99 9 9

9999 99 «9

9 9 9 9 9 9

9 9 9 9 9 9

9 99 99· 04«

9 9 9 9 9

99 99 9»

Packaging ethyl cellulose 9,-6. Cítroflex® 2 2.3 ,- talc *. 7.2- f-1 1 34 g-

Since there are no suitable methods to measure the release of the bioactive protein as a function of time, the retardation time was determined visually by the appearance of the coated tablets (like opening the lid of the box).

·. An in vitro dissolution test performed with 6 coated tablets on a USP II device with a half exchange of media (pH = 1.2 and then target = 6.8) and a stirrer rotation speed of 50 rpm gave lag times as stated following, table. '

tablet no. 1 No. 2 No. 3 No. 4' No. 5 No. '-6 time delay (minutes)' 231- ' ' 201 . . 22S 22'3 223 '218·'

After releasing the core content, the bioactive protein content was measured. Turns out there was a quantity available. approximately 25% (i.e. 7.5 .gg per tablet) of bioactive protein. - · .· The conclusion from these experiments is that it is possible to prepare an oral preparation with a delayed pulse release according to the present invention containing a bioactive protein. ' ·

I* »·*» «4 I* ··*» »* «4

4 4· 4 49*4

4* 44 * 4944

4994» 9 94 4 9 4 049

4 4 4 4 ♦ 4

944 44 4* 44 44

7/

Claims (8)

PATENT CLAIMS 1. Oral preparation with delayed pulse. releasing -v-y-z-n-a-n-a-j-i-c-i-e-e-that-obs-a-huj-e-L-ts-ova-containing core , one, or., several. The core comprises one or more carriers for (instantaneous pulse release, but does not have substantial swelling properties if the active substance is surrounded by the shell, the release of the active substance from the core being caused by the rupture of the shell after some precise delay time). is exposed to digestive., juices. \ A delayed pulse release oral formulation comprising a compressed core comprising 'one' or several active substances, surrounded by a container containing one or more polymeric packaging materials, wherein: the release of the active agent from the core is caused by the rupture of the envelope after a certain precise time from time to time, and said core comprises one or more carriers for (instantaneous) pulse. it does not have substantial swelling properties when exposed to digestive juices, and said polymeric coating materials are substantially insoluble and / or. ... does not disintegrate due to digestive juices. ' .... . ' 3. The delayed pulse release oral preparation of claim 2. wherein the coating comprises 2 to 20% of a water-soluble softening agent and an effective amount of the brittleness agent. • · β 43 β 9 5 β β · 5β ® β · · · ¢ ¢ ¢ ¢ · · · · · · · ·· · * «·· · ·· ·· ·· ·· - 37 The delayed pulsatile release oral formulation of claim 3, wherein the water-soluble emollient is selected from the group consisting of triethyltin, tributylcitrate, propylene glycol. polyethylene glycol, tracetin and sodium lauryl sulphate. .3. _r 5. The delayed release oral preparation according to claims 3 and 4, wherein the water-soluble emollient is triethyltinate. . _: Sixth Oral Delayed Release formulation according to claim ^pulsnlm: 3-5 characterized -C uj .1 'Í c' by the brittleness-inducing agent is added in an amount of 3 'or analytically 60%. 7) Oral ^L .opožděným 'pulsed release formulations according to claim 6 wherein t -se i.m. the brittleness-inducing agent is selected from the group comprising 20-40% talc, 3-25% of aerosil and ·' 5 60% .When magnesium stearate. . Oral preparation ‘Delayed. pulse releasing according to of claim 7 you of n- a No u 'j I C s s, e. wherein the agent causing fragility is -20 to 40 % -talku.  t ' Oral preparation sopožděným • pulse .Releasing according to claims to 8 v y z 1 s e t ·· í m that polymerní packaging . material se v basically- composed by. from ethyl cellulose. • this »this ···· · · · to · - · to · to · to · to · to · to · · to · • to ·· 38 A delayed pulse release oral preparation according to claims -1 to 9. u. wherein the formulation is in a form with a diameter greater than 2 mm, preferably. greater than 5 mm. An oral preparation with delayed pulse release according to any of the preceding claims. wherein the active ingredient is a pharmaceutical composition selected from the group consisting of antiasis, cardiac drugs, vasodilators, anti-arthritic agents, and lesser anti-depressants; 'preparations'. prótizánětlivé. gastrointestinal preparations, anti-ulcer preparations, anti-arthritic, antiarrhythmic, anti-arthritic, anti-arthritis and anti-tonsillitis preparations. 1.2. The oral delayed-release formulation of claims 10 to 10, wherein the active agent is a biologically active compound selected from the group consisting of proteins, peptides, enzymes, and oligonucleotides. vaccine. The delayed pulse release oral preparation of claim 12. of. at No. Ujica '.se by ¹ biologically active · látka'j e vaccine. The delayed pulse release oral preparation of claim 13, wherein said vaccine is an influenza vaccine. 9 «« | 99 · 99 99 9 9 9> 999 9 99 99 9 9 · 9 99999 9 09 9 * 9 9 9 9 9 9 9 9 "9 99 99 99 99 _r 15. A delayed pulse release oral preparation according to claims 1 to 14, characterized in that said &quot; delayed pulse release oral preparation &quot; has a certain delay time and is combined in one. The tobc-bce-s-p-er-orally-by-sublingual (s) (s) team (s), by release and / or one or by several peroretic ones. delayed pulse release preparations‘with a different delay time. . ' 16. Oral preparation, with delayed pulse release according to 1 claims up to 14 ' The delayed release is surrounded by the delayed preparation. oral o, i m, following a pulse preparation with (immediate) pulse release. 17 ·. Method of preparation of oral preparation with delayed pulse. release according to claims 1 and tr n Ί4 mares i 'c s ^r t in that (a) core, se. molded from a composition comprising one or more active agents, and one or more (immediate) release carriers; and b) the molded core is coated with a coating of a mixture of packaging materials, said core and said coating having the properties and / or the composition according to claims 1 to 14. 0 · 0 · 000 00 000 000 0 000 00 00 0 0 - 40 18. A method of preparing an Oral Delayed pulsnímuvolňováním according to claims 15 to 15 wherein _R S2'CÍ.m ZG (a) the core is compressed from mixtures comprising one or more active substances and one or more (immediate) pulse release carriers; (b) the molded core is coated with a sheath of. mixtures packaging ma.teriálů a c) first oral ¹ - preparation with (instant) pulse relaxing (i) combine the capsule with pérorélním. preparation (immediate) pulse release and / or one or more 'delayed pulse release oral preparations with · different delay times',' or. ii) surround with the (immediate) formulation. pulse release and a mixture of packaging materials, wherein said core and said packaging. have the properties and / or compositions according to claims 15 to 16.. .